Congenital or fetal hydrocephalus (FH) is one of the most common neurological disorders of newborns. It is often associated with head enlargement, accumulating cerebrospinal fluid (CSF) and neurological impairment. There are no curative therapies for hydrocephalus and therapies are generally limited to palliative, surgical approaches that utilize shunts to remove excess CSF. This proposal builds upon a recently reported link between a lipid signaling system and FH: lysophospholipids (LPs) that include LPA (lysophosphatidic acid), S1P (sphingosine 1-phosphate), and other related LPs. Present in blood, LPs could be part of the explanation for the observation that fetal bleeding increases the incidence of FH. This study will develop and characterize an animal model that recapitulates multiple, comorbid histological phenomena in the brain while producing FH. It will also determine the linkage between animal models and human FH by examining human FH CSF and brain tissue. Over a 5-year period, three aims will test the hypothesis that LP receptor mechanisms contribute to the etiology and therapeutic tractability of human FH. Aim 1 will identify LPA chemical forms, including precursors and metabolites, from human hydrocephalic CSF, and assess their ability to induce FH and co-morbid CNS structural changes. Samples obtained through clinical collaborators and brain banks will be assessed towards establishing links between human FH and these animal models. Aim 2 will determine cellular and molecular mechanisms contributing to the development of LPA-induced FH and comorbid changes, and assess their prevention or therapy via targeted agents. This aim will provide new mechanistic insights that have therapeutic potential. Aim 3 will identify new LP mechanisms with therapeutic potential contributing to FH and associated co-morbid changes. This aim could expand the lipid influences on FH and offer distinct therapeutic targets for its treatment. Completion of these aims could open new mechanistic and therapeutic understanding for this common and debilitating disorder.